Drugs in Liver Disease

Dr. Saed M. Aldalaen Mutah university, Medicine faculty, Jordan 2009

Liver

Liver disease alters response to drugs Drugs may alter liver function Drugs used by patients with severe liver disease should be kept to minimum Main problems may occur in patients with:

Jaundice Ascites Evidence of encephalopathy

Jaundice in a man with hepatic failure

Jaundice in a man caused by hepatitis A

Jaundice also known as icterus, is a yellowish discoloration of the skin, the conjunctival membranes over the sclerae (whites of the eyes), and other mucous membrane caused by hyperbilirubinemia (increased levels of billirubin in the blood). This hyperbilirubinemia subsequently causes increased levels of billirubin in the extracellular fluids. The bilirubin results from the breakup of the hemoglobin of dead red blood cells; normally, the liver removes bilirubin from the blood and excretes it through bile
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Liver

Liver is the most important organ of metabolism of drugs Metabolites may be inactive, active or toxic Liver is exposed to drugs in higher concentration than other organs as most drugs are administered orally & have to pass through liver after absorption Liver is susceptible to injury Liver disease can produce abnormal drug handling & response
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Effects of liver disease on drugs

1. Pharmacodynamic alterations: Patients with severe liver disease show abnormal response to drugs:

Increased effects of anticoagulant drugs Increased response to drugs acting on CNS Increased sodium retention following NSAIDs

1. Pharmacodynamic changes

Reduced clotting: Reduced hepatic synthesis of clotting factors As indicated by prolonged prothrombin time Increases sensitivity to oral anticoagulants:

Warfarin resulting in increased risk of bleeding

1. Pharmacodynamic changes

Hepatic encephalopathy In severe liver disease (e.g. cirrhosis, hepatitis) many drugs can impair cerebral function & may precipitate hepatic encephalopathy as:

Sedative-hynotics Opioid analgesics Hypokalemia producing diuretics (Thiazides) Drugs causing constipation (Al Hydroxide)

1. Pharmacodynamic changes
Fluid overload Oedema and ascites (fluid in the peritoneal cavity) in chronic liver disease may be exacerbated by drugs that result in fluid retention as

NSAIDs, corticosteroids

Ascites (also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum) is an accumulation of fluid in the peritoneal cavity. Although most commonly due to cirrhosis and severe liver disease, its presence can portend other significant medical problems.
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2. Pharmacokinetic changes

Impaired drug metabolism Liver disease may result in impairment of hepatic metabolism of drugs causing:

Reduced clearance of drugs & increased toxicity e.g. warfarin

NB: Liver function tests (LFT) are poor guide to the capacity of the liver to metabolize drugs & relying on them alone is not sufficient to predict the extent of impairment of drug metabolism
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e.g. Liver diseases

Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons, autoimmunity or hereditary conditions. Cirrhosis is the formation of fibrous tissue in the liver, replacing dead liver cells. The death of the liver cells can for example be caused by viral hepatitis, alcoholism or contact with other liver-toxic chemicals. Haemochromatosis, a hereditary disease causing the accumulation of Fe in the body, eventually leading to liver damage. Cancer of the liver (primary hepatocellular carcinoma or cholangiocarcinoma and metastatic cancers, usually from other parts of the GIT). Wilson's disease, a hereditary disease which causes the body to retain Cu. Primary sclerosing cholangitis, an inflammatory disease of the bile duct, likely autoimmune in nature. Primary biliary cirrhosis, autoimmune disease of small bile ducts. Budd-Chiari syndrome, obstruction of the hepatic vein. Gilbert's syndrome, a genetic disorder of bilirubin metabolism. Glycogen storage disease type II, the build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system. There are also many pediatric liver disease, including biliary atresia, alpha-1 antitrypsin deficiency, alagille syndrome, and progressive familial intrahepatic cholestasis, to name but a few.
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Healthy liver

cirrhotic liver

Healthy liver
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Liver infected by type C virus

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The dark reddish brown color of liver surface is characteristic in hemochromatosis. The liver surface of this case shows granular change, suggesting the presence of a fine nodular formation in liver histology

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The liver in the non-cirrhotic stage of Wilson's disease is usually enlarged, and shows the characteristic spotty pigmentation. These spots are believed to be caused by Cu deposition in liver parenchyma.

Biliary Atresia - a serious disease of the very young infant. This disease results in inflammation and obstruction of the ducts which carry bile from the liver into the intestine.

Primary sclerosing cholangitis

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2. Pharmacokinetic changes
Accumulation Some drugs as Rifampicin & fusidic acid excreted in bile unchanged
toxicity

may accumulate in obstructive jaundice causing

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3. Alterations in liver blood flow & metabolism

Reduced blood flow in liver disease leads to: Reduced drug delivery to liver cells Drugs with high first pass metabolism: Removal of drugs will be less Increased systemic bioavailability Doses should be smaller Therefore initial & maintenance doses of such drugs should be smaller e.g. opioid analgesics

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4. Alteration in drug-protein binding

Hypoproteinaemia (Hypoalbuminaemia) result in: Reduced protein-bound fraction Increased free fraction Leading to increased:
warfarin, prednisolone)
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Drug effects & increased toxicity For highly protein-bound: more than 90% (phenytoin,

Drug prescription in liver disease

In mild liver disease & stable liver: prescribing is safe Prescription should be very careful in patients with severe liver disease and:

Impaired hepatic synthesis (as hypoalbuminaemia & reduced clotting factor) Hepatic encephalopathy Fluid retention Renal impairment Drugs with high protein binding, low therapeutic index and CNS depressants

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Drug prescription in liver disease

For drugs with significant liver metabolism, a good approach is:

To reduce dose to 25-50 % Monitor response carefully Examples:

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Drug prescription in liver disease

CNS depressants: avoid or used cautiously Opioids: can precipitate hepatic encephalopathy in patients with liver disease and if required postoperatively the dose is reduced by 50% Codeine causes constipation & can precipitate encephalopathy NSAID: precipitate fluid retention & GIT bleeding CVS drugs: lipid-soluble -blockers avoided
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Drug prescription in liver disease

Na containing antacids: fluid retention Al antacids: cause constipation & may precipitate encephalopathy. Oral contraceptive pills (OCP): may exacerbate cholestatic liver disease & jaundice

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Hepatotoxic drugs

Hepatotoxicity is either:

Dose-related or Idiosyncratic

Drugs causing dose-related toxicity may do so at lower doses than in those with normal liver Drugs producing idiosyncratic reactions do so more frequently in patients with liver disease So these drugs should be avoided or used very carefully
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Drug-induced liver damage

Type A (Augmented): Liver damage is dose-dependent E.g. Centrilobular necrosis: paracetamol toxicity Liver failure: high doses tetracycline Hepatocellular necrosis: salicylates

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Drug-induced liver damage

Type B (Bizarre; idiosyncratic): Occurs with therapeutic doses due to production of hepatotoxic reactive metabolites or due to immunological reaction against liver cell antigens. May include: Acute hepatocellular necrosis: halothane Cholestasis: erythromycin, chlorpromazine, glibenclamide
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Drug-induced liver damage

Type C (Continued use):

Benign liver tumour: OCP (>5 yrs) Chronic active hepatitis: methyldopa & INH Hepatic cirrhosis: methotrexate in psoriasis

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